Implantable device and methods for delivering drugs and other substances to treat sinusitis and other disorders

ABSTRACT

Implantable devices and methods for delivering drugs and other substances to locations within the body of a human or animal subject to treat or diagnose sinusitis and a variety of other disorders. The invention includes implantable substance delivery devices that comprise reservoirs and barriers that control the rate at which substances pass out of the reservoirs. The delivery devices may be advanced into the body using guidewires, catheters, ports, introducers and other access apparatus. In some embodiments the delivery devices may be loaded with one or more desired substance before their introduction into the body. In other embodiments the delivery devices are loaded and/or reloaded with a desired substance after the delivery device has been introduced into the body.

FIELD OF THE INVENTION

The present invention relates generally to medical devices and methodsand more particularly to substance delivering implants and methods fortreating a broad range of disorders including but not limited tosinusitis and other ear, nose and throat disorders.

BACKGROUND

The paranasal sinuses are cavities formed within the bones of the face.The paranasal sinuses include frontal sinuses, ethmoid sinuses,sphenoidal sinuses and maxillary sinuses. The paranasal sinuses arelined with mucous-producing epithelial tissue. Normally, mucous producedby the linings of the paranasal sinuses slowly drains out of each sinusthrough an opening known as an ostium, and into the nasopharnyx.Disorders that interfere with drainage of mucous (e.g., occlusion of thesinus ostia) can result in a reduced ability of the paranasal sinuses tofunction normally. This results in mucosal congestion within theparanasal sinuses. Such mucosal congestion of the sinuses can causedamage to the epithelium that lines the sinus with subsequent decreasedoxygen tension and microbial growth (e.g., a sinus infection).

The nasal turbinates are three (or sometimes four) bony processes thatextend inwardly from the lateral walls of the nose and are covered withmucosal tissue. These turbinates serve to increase the interior surfacearea of the nose and to impart warmth and moisture to air that isinhaled through the nose. The mucosal tissue that covers the turbinatesis capable of becoming engorged with blood and swelling or becomingsubstantially devoid of blood and shrinking, in response to changes inphysiologic or environmental conditions. The curved edge of eachturbinate defines a passageway known as a meatus. For example, theinferior meatus is a passageway that passes beneath the inferiorturbinate. Ducts, known as the nasolacrimal ducts, drain tears from theeyes into the nose through openings located within the inferior meatus.The middle meatus is a passageway that extends inferior to the middleturbinate. The middle meatus contains the semilunar hiatus, withopenings or ostia leading into the maxillary, frontal, and anteriorethmoid sinuses. The superior meatus is located between the superior andmedial turbinates.

Nasal polyps are benign masses that grow from the lining of the nose orparanasal sinuses. Nasal polyps often result from chronic allergicrhinitis or other chronic inflammation of the nasal mucosa. Nasal polypsare also common in children who suffer from cystic fibrosis. In caseswhere nasal polyps develop to a point where they obstruct normaldrainage from the paranasal sinuses, they can cause sinusitis.

The term “sinusitis” refers generally to any inflammation or infectionof the paranasal sinuses. Sinusitis can be caused by bacteria, viruses,fungi (molds), allergies or combinations thereof.

Various drugs have been used to treat sinusitis, including systemicantibiotics. Intranasal corticosteroid sprays and intranasaldecongestant sprays and drops have also been used. However, the use ofintranasal sprays and drops by most patients does not result in the drugactually entering the affected intranasal sinuses. Rather, such spraysand drops typically contact only tissues located within the nasalcavity. The introduction of drugs directly into the sinuses has beenproposed by others, but has not become a widely used treatmenttechnique.

For example, U.S. Patent Application Publication 2004/0116958A1(Gopferich et al.) describes a tubular sheath or “spacer” formed ofbiodegradable or non-biodegradable polymer that, prior to insertion inthe patient's body, is loaded with a controlled amount of an activesubstance, such as a corticosteroid or anti-proliferative agent. Surgeryis performed to create a fenestration in a frontal sinus and the sheathis inserted into such fenestration. Thereafter, the sheath which hasbeen preloaded with the active substance is inserted into the surgicallycreated fenestration where it a) deters closure of the surgicallycreated fenestration, b) serves as a conduit to facilitate drainage fromthe sinus and d) delivers the active substance. The sheath of U.S.Patent Application Publication 2004/0116958A1 (Gopferich et al.) remainssubstantially in a single configuration (i.e., it does not transitionbetween a collapsed configuration and an expanded configuration)although it may be coated with a material that swells when in contactwith mucous or body fluid. In some embodiments, the sheath is formed ofmultiple layers of polymeric material, one or more of which is/areloaded with the active substance and one or more of which is/are free ofthe active substance. In other embodiments, the sheath has a “hollowbody” which forms a reservoir system wherein the active substance iscontained and a membrane which controls the release of the activesubstance from the reservoir. In some embodiments, the sheath may beanchored by causing the end of the sheath that extends into the sinus toswell or otherwise enlarge.

Also, Min, Yang-Gi, et al., Mucociliary Activity and Histopathology ofSinus Mucosa in Experimental Maxilary Sinusitis: A Comparison ofSystemic Administration of Antibiotic and Antibiotic Delivery byPolylactic Acid Polymer, Laryngoscope, 105:835-842 (August 1995)describes experiments wherein experimental sinusitis was induced inthree groups of rabbits by “pasting” the natural sinus ostia, forming anincision and small bore hole made in the anterior wall of the sinus,introducing pathogenic microbes through the bore hole and then closingthe incision. Five days after introduction of the pathogenic microbes,the natural sinus ostia were reopened and the rabbits were divided intothree (3) groups. Group 1 (control) received no treatment. Group 2received repeated intramuscular injections of ampicillin. In the animalsof Group 3, 1.5 cm×1.5 cm sheets of polylactic acid polymer (PLA) filmcontaining ampicillin (0.326 mg/sheet) were rolled up and insertedthrough the natural ostia into the infected sinuses. Thereafter,measurements of mucocilliary transport speed were made and the tissueslining the affected sinuses were examined histopathologically. Theauthors concluded that the therapeutic effect observed in the animalsthat had received intrasinus implants of PLA/Ampicillin film (Group 3)was significantly better that that observed in the untreated controlanimals (Group 1) or those that has received repeated intramusculardoses of ampicillin (Group 2).

U.S. Pat. No. 3,948,254 (Zaffaroni) describes implantable drug deliverydevices comprising a drug reservoir surrounded by a microporous wall.The reservoir may be formed of a solid drug carrier that is permeable topassage of the drug. The rate of passage of the drug through the wallmay be slower than the rate at which the drug passes through the soliddrug carrier that forms the reservoir. U.S. Pat. No. 3,948,254(Zaffaroni) describes a number of applications for the implantable drugdelivery devices including placement in a nasal passage. Specifically,U.S. Pat. No. 3,948,254 (Zaffaroni) claimed a nasal delivery device fordispensing a drug within a nasal passage at a controlled rate whereinthe nasal device is comprised of (a) a wall defining the devicedimensioned for insertion and placement within a nasal passage, with thewall formed of a nasal acceptable microporous material, (b) a reservoirsurrounded by the wall and comprised of a solid carrier permeable todrug and containing drug in an amount sufficient for the device to meterit at a continuous and controlled rate for a prolonged period of timefrom the device, (c) a liquid medium permeable to the passage of drug bydiffusion charged in the micropores, and (d) wherein the device releasesdrug when in a nasal environment by passage of drug from the carrier andthrough the liquid to the exterior of the device to produce a usefulresult. The entire disclosure of U.S. Pat. No. 3,948,254 (Zaffaroni) isexpressly incorporated herein by reference.

Other publications have also reported that introduction of drugsdirectly into the paranasal sinuses is effective in the treatment ofsinusitis. See, Tarasov, D. I., et al., Application of Drugs Based onPolymers in the Treatment of Acute and Chronic Maxillary Sinusitis,Vestn Otorinolaringol. Vol. 6, Pages 45-7 (1978). Also, R. Deutschmann,et al., A Contribution to the Topical Treatment of [Maxillary] SinusitisPreliminary Communication, Stomat. DDR 26 (1976), 585-592 describes theplacement of a resorbable drug delivery depot within the maxillary sinusfor the purposes of eluting drugs, specifically Chloramphenicol. In thisclinical series a water soluable gelatin was used as carrier and wasmixed with the drug prior to application and introduced as a mass intothe sinus. Since the substance had little mechanical integrity anddissolved in a relatively short timeframe, to achieve a therapeuticeffect, the author suggested that it must be instilled every 2 to 3days. An alternative to gelatin could be a sponge loaded with thetherapeutic substance as suggested in U.S. Pat. No. 6,398,758 (Jacobsen,et al.). In this patent directed at delivering a sustained releasedevice against the wall of a blood vessel, a hollow cylindrical spongeis loaded with drug and pressed against the wall. This allows the drugto contact the wall while sustaining blood flow within the center of thelumen. Further, a skin is provided to direct the drug into the walls ofthe blood vessel and prevent drug from flowing into the lumen. Whilesponges loaded with drug at the time of their application do permit somedegree of sustained release, the time required to load them alsocorrelates closely the time over which they will elute substance. Thus,if delivery is required for a longer period of time additionalmechanisms must be employed to regulate their release.

There are also several examples in the patent literature where varioussustained release mechanisms have generally been proposed using systemswith pre-incorporated drugs into matrices or polymers. These includeU.S. Pat. No. 3,948,254 (Zafferoni), U.S. 2003/0185872A2 (Kochinke), WO92/15286 (Shikani), and U.S. Pat. No. 5,512,055 (Domb, et al.). Ingeneral, these references discuss various materials and structures thatmay be used to construct sustained drug delivery vehicles and provide agood overview of the state of sustained drug delivery art. While helpfulin laying out certain materials and schemes for creating sustainedrelease systems for drugs, each of these references, however, do notdescribe specific methods, means or structures which would permit themto be easily adapted for intended uses in the targeted in thisapplication.

There remains a need in the art for the development of new devices andmethods for delivering drugs and other therapeutic or diagnosticsubstances into paranasal sinuses or other locations within the body forthe treatment of sinusitis or other diseases and disorders.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a method anddevice for delivering a substance to a location within the body of ahuman or animal subject (e.g., within the nose, paranasal sinus, ostiumof a paranasal sinus, eustachian tube, etc.) to diagnose or treat adisorder (e.g., sinusitis or another disorder of the ear, nose orthroat). In general, this method comprises the steps of: A) providing animplantable substance delivery device that comprises i) a substancereservoir that may subsequently be loaded with a substance that istherapeutically effective to diagnose or treat the disorder and ii) abarrier that will limit the rate at which a substance will flow out ofthe reservoir; B) providing a substance that is useable to diagnose ortreat the disorder; C) introducing a quantity of the substance into thereservoir; and D) implanting the device at a location within thesubject's body such that the substance will be delivered by theimplanted device to a location within the subject's body. In someapplications, the physician may load a desired therapeutic or diagnosticsubstance into the reservoir before the device is implanted in thesubject's body. In other applications, the physician may load a desiredtherapeutic or diagnostic substance into the reservoir after the devicehas been implanted in the subject's body. The device may bebiodegradable or non-biodegradable and may or may not be removed fromthe body after it has remained implanted for a desired period of time.The barrier of the device may comprise an aperture, membrane (e.g.,semi-permeable membrane) or other structure that allows one or moresubstances having certain key property or properties to pass through thebarrier at approximately a known rate. Examples of the key propertiesthat may determine a substance's ability to pass through the barrier atapproximately the known rate include but are not limited to viscosity ora range of viscosities, molecular weight or range or molecular weights,osmolarity or range of osmolarities, osmolality or range ofosmolalities, electrical charge, presence of a chemical group or atom,hydrophilic or hydrophibic properties, the size and/or shape ofmolecules, etc. Thus, a physician and/or pharmacist may, in some cases,select a barrier and select or specially formulate a substance thatpossess a particular key property relative to the selected barrier, suchthat the substance will be delivered through the barrier at an intendeddelivery rate.

Further in accordance with the invention the reservoir of the device maycomprise a hollow cavity, porous material (e.g., an absorptive polymerfoam) or combination thereof. The barrier may comprise a membrane oropening that surrounds, substantially surrounds, partially surrounds oris located next to the reservoir such that substance contained withinthe reservoir will pass through the barrier at a controlled rate.

Still further in accordance with the invention, the implantablesubstance delivery device may be configured such that, at least when thereservoir is loaded with the substance, the outer surface of the devicewill have peaks and valleys such that the peaks are in contact withadjacent tissues or other anatomical structure(s) and the valleys remainspaced away from adjacent tissues or other anatomical structures so asnot to interfere with the physiological function of those tissues orother anatomical structures. Such embodiments of the device may beimplanted in areas of the nose or paranasal sinuses lined with ciliatedmucosal tissue and the surface(s) of the device within the valleys willremain far enough away from the adjacent ciliated mucosa as to notinterfere with mucociliary transport by such tissue. The diameter orcross-sectional configuration of the device may vary along its length ormay be shaped in a conical, frustoconical or curvilinear (e.g.,hourglass) shape. Also, the device may have region(s) of differinghardness (e.g., durometer), flexural properties (e.g., stiffness orflexibility) or compliance and such properties may change in response tothe presence or absence of the therapeutic or diagnostic substanceand/or contact or non-contact with body fluids (e.g., mucous) or otherconditions present at the intended site of implantation.

Further aspects, details and embodiments of the present invention willbe understood by those of skill in the art upon reading the followingdetailed description of the invention and the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic cut-away showing of a human head having acatheter-based substance delivery system of the present inventioninserted therein to deliver a substance delivery implant into the leftfrontal sinus.

FIG. 2 is a longitudinal sectional view of one embodiment of animplantable substance delivery device of the present invention having agenerally round cross-sectional configuration and a self-sealing fillsite.

FIG. 2A is a longitudinal sectional view of the device of FIG. 2 as itis being filled with a substance.

FIG. 2B is a longitudinal sectional view of another embodiment of animplantable substance delivery device of the present invention having afill tube that extends from its fill site.

FIG. 2C is a sectional view of a paranasal sinus having an implantablesubstance delivery device of the present invention implanted therein.

FIG. 3 is a perspective view of another embodiment of an implantablesubstance delivery device of the present invention having across-sectional configuration that provides discrete projections thatcontact the surrounding anatomical structure(s) while space remainsbetween the remainder of the device and the surrounding anatomicalstructure(s).

FIG. 3A is a cross sectional view through line 3A-3A of FIG. 3.

FIG. 4 is a perspective view of another embodiment of an implantablesubstance delivery device of the present invention having a frame, aporous core, an outer barrier layer and a cross-sectional configurationthat provides for discrete areas of contact between the implantedsubstance delivery device and the surrounding anatomical structure(s).

FIG. 4A is an end view of the device of FIG. 4.

FIG. 4B is a partial cross sectional view of an implantable substancedelivery device having a frame, a porous core and an outer barrierlayer, wherein the porous core is disposed within the frame and thebarrier layer is subsequently applied over the frame.

FIG. 4C is a partial cross sectional view of an implantable substancedelivery device having a frame, a porous core and an outer barrierlayer, wherein the frame is integral of the porous core and the barrierlayer is disposed on the outer surface of the porous core.

FIG. 5 is a perspective view of a screw-shaped substance delivery deviceof the present invention positioned within an anatomical passageway.

FIG. 5A is a cross sectional view through line 5A-5A of FIG. 5.

FIG. 6A is a perspective view of a helical substance delivery device ofthe present invention positioned within an anatomical passageway.

FIG. 6B is a perspective view of another embodiment of a substancedelivery device of the present invention comprising a plurality ofsubstantially parallel substance eluting strut members.

FIG. 6C is a schematic diagram showing the device of FIG. 6B implantedwithin a paranasal sinus.

FIG. 6D is a schematic diagram showing a modified version of the deviceof FIG. 6B implanted within a paranasal sinus.

FIG. 7 is a side view of a substance delivery device of the presentinvention that is configured for implantation and retention within aparanasal sinus.

FIG. 7A shows the substance delivery device of FIG. 7 after it has beenpositioned within a paranasal sinus but before being loaded withtherapeutic or diagnostic substance.

FIG. 7B shows the substance delivery device of FIG. 7 after it has beenpositioned within a paranasal sinus and after it has been loaded withtherapeutic or diagnostic substance.

FIG. 8A shows a fill tube for a substance delivery implant device of thepresent invention having a fill tube with a valve for preventing thesubstance from back-flowing out of the fill tube.

FIG. 8B shows a substance delivery implant device of the presentinvention having a fill tube with a clip for preventing the substancefrom back-flowing out of the fill tube.

FIG. 8C shows a substance delivery implant device of the presentinvention having a fill tube with a ligature for preventing thesubstance from back-flowing out of the fill tube.

FIG. 8D shows a substance delivery implant device of the presentinvention having a fill port with an adhesive applicator for applyingadhesive to plug the fill port thereby preventing the substance fromback-flowing out of the fill port.

FIG. 8E shows a substance delivery implant device of the presentinvention having a fill tube that is doubled over and clipped to preventthe substance from back-flowing out of the fill tube.

FIG. 9 is a longitudinal sectional view of another embodiment of animplantable substance delivery device according to the presentinvention.

FIG. 9A is a perspective view of a system comprising the implantablesubstance delivery device of FIG. 9 in combination with a deliverycatheter device that is useable for implantation of the implantablesubstance delivery device within the body of a human or animal subject.

FIG. 9B shows the system of FIG. 9A after the delivery catheter devicehas been detached from the implanted substance delivery device.

FIG. 10A is an exploded view of a system for delivery and implantationof a substance eluting filament in accordance with the presentinvention.

FIG. 10B is a schematic diagram showing an example of a method by whichthe system of FIG. 10A may be used to implant the substance elutingfilament within a paranasal sinus.

FIG. 11A is a cut-away side view of a catheter system having a secondlumen that is useable for implanting an implantable substance deliverydevice or drug eluting filament by tracking over a previously insertedguidewire.

FIG. 11B is a cut-away side view of a catheter system adapted forover-the-wire delivery of an implantable substance delivery device ordrug eluting filament that has a guidewire lumen extendinglongitudinally therethrough.

FIGS. 12A-12F schematic diagrams showing steps in a procedure for a)access to and enlargement of the ostium of a paranasal sinus and b)implantation of an implantable substance delivery device of the presentinvention within the enlarged ostium and paranasal sinus.

DETAILED DESCRIPTION

The following detailed description and the accompanying drawings areintended to describe some, but not necessarily all, examples orembodiments of the invention only. This detailed description and theaccompanying drawings do not limit the scope of the invention in anyway.

The human nose has right and left nostrils or nares which lead intoseparate right and left nasal cavities. The right and left nasalcavities are separated by the intranasal septum, which is formedsubstantially of cartilage and bone. Posterior to the intranasal septum,the nasal cavities converge into a single nasopharyngeal cavity. Theright and left Eustachian tubes (i.e., auditory tubes) extend from themiddle ear on each side of the head to openings located on the lateralaspects of the nasopharynx. The nasopharynx extends inferiorly over theuvula and into the pharynx. As shown in FIG. 1, paranasal sinuses areformed in the facial bones on either side of the face. The paranasalsinuses open, through individual openings or ostia, into the nasalcavities. The paranasal sinuses include frontal sinuses FS, ethmoidsinuses ES, sphenoidal sinuses SS and maxillary sinuses MS.

The present invention provides implantable devices that may bepositioned within a naturally occurring or man-made anatomical cavity orpassageway such as a nostril, nasal cavity, meatus, ostium, interior ofa sinus, etc. to deliver a diagnostic or therapeutic substance totissues located adjacent to or near the implanted device. Certainnon-limiting examples of the present invention are shown in FIGS. 1-12Fand described in detail herebelow. Although certain examples shown inthese drawings are targeted to the paranasal sinuses and nasal cavities,the devices and methods of the present invention are useable in a widerange of applications in various area of the body, including but notlimited to natural or man made orifices and passageways, subcutaneouslocations, intravascular or intracardiac locations and locations withinthe gastrointestinal tract.

The term “diagnostic or therapeutic substance” as used herein is to bebroadly construed to include any feasible drugs, prodrugs, proteins,gene therapy preparations, cells, diagnostic agents, contrast or imagingagents, biologicals, etc. Such substances may be in bound or free form,liquid or solid, colloid or other suspension, solution or may be in theform of a gas or other fluid or nan-fluid. For example, in someapplications where it is desired to treat or prevent a microbialinfection, the substance delivered may comprise pharmaceuticallyacceptable salt or dosage form of an antimicrobial agent (e.g.,antibiotic, antiviral, antiparacytic, antifungal, etc.), acorticosteroid or other anti-inflammatory (e.g., an NSAID), adecongestant (e.g., vasoconstrictor), a mucous thinning agent (e.g., anexpectorant or mucolytic), an agent that prevents of modifies anallergic response (e.g., an antihistamine, cytokine inhibitor,leucotriene inhibitor, IgE inhibitor, immunomodulator), etc.

Some nonlimiting examples of antimicrobial agents that may be used inthis invention include acyclovir, amantadine, aminoglycosides (e.g.,amikacin, gentamicin and tobramycin), amoxicillin,amoxicillin/clavulanate, amphotericin B, ampicillin,ampicillin/sulbactam, atovaquone, azithromycin, cefazolin, cefepime,cefotaxime, cefotetan, cefpodoxime, ceftazidime, ceftizoxime,ceftriaxone, cefuroxime, cefuroxime axetil, cephalexin, chloramphenicol,clotrimazole, ciprofloxacin, clarithromycin, clindamycin, dapsone,dicloxacillin, doxycycline, erythromycin, fluconazole, foscarnet,ganciclovir, atifloxacin, imipenem/cilastatin, isoniazid, itraconazole,ketoconazole, metronidazole, nafcillin, nafcillin, nystatin, penicillin,penicillin G, pentamidine, piperacillin/tazobactam, rifampin,quinupristin-dalfopristin, ticarcillin/clavulanate,trimethoprim/sulfamethoxazole, valacyclovir, vancomycin, mafenide,silver sulfadiazine, mupirocin (e.g., Bactroban Nasal®, GlaxoSmithKline, Research Triangle Park, N.C.), nystatin,triamcinolone/nystatin, clotrimazole/betamethasone, clotrimazole,ketoconazole, butoconazole, miconazole, tioconazole, detergent-likechemicals that disrupt or disable microbes (e.g., nonoxynol-9,octoxynol-9, benzalkonium chloride, menfegol, and N-docasanol);chemicals that block microbial attachment to target cells and/orinhibits entry of infectious pathogens (e.g., sulphated and sulponatedpolymers such as PC-515 (carrageenan), Pro-2000, and Dextrin 2Sulphate); antiretroviral agents (e.g., PMPA gel) that preventretroviruses from replicating in the cells; genetically engineered ornaturally occurring antibodies that combat pathogens such as anti-viralantibodies genetically engineered from plants known as “plantibodies;”agents which change the condition of the tissue to make it hostile tothe pathogen (such as substances which alter mucosal pH (e.g., BufferGel and Acidform); non-pathogenic or “friendly” microbes that cause theproduction of hydrogen peroxide or other substances that kill or inhibitthe growth of pathogenic microbes (e.g., lactobacillus); antimicrobialproteins or peptides such as those described in U.S. Pat. No. 6,716,813(Lin et al,.) which is expressly incorporated herein by reference orantimicrobial metals (e.g., colloidal silver).

Additionally or alternatively, in some applications where it is desiredto treat or prevent inflammation the substances delivered in thisinvention may include various steroids or other anti-inflammatory agents(e.g., nonsteroidal anti-inflammatory agents or NSAIDS), analgesicagents or antipyretic agents. For example, corticosteroids that havepreviously administered by intranasal administration may be used, suchas beclomethasone (Vancenase® or Beconase®), flunisolide (Nasalide®),fluticasone proprionate (Flonase®), triamcinolone acetonide (Nasacort®),budesonide (Rhinocort Aqua®), loterednol etabonate (Locort) andmometasone (Nasonex®). Other salt forms of the aforementionedcorticosteroids may also be used. Also, other non-limiting examples ofsteroids that may be useable in the present invention include but arenot limited to aclometasone, desonide, hydrocortisone, betamethasone,clocortolone, desoximetasone, fluocinolone, flurandrenolide, mometasone,prednicarbate; amcinonide, desoximetasone, diflorasone, fluocinolone,fluocinonide, halcinonide, clobetasol, augmented betamethasone,diflorasone, halobetasol, prednisone, dexamethasone andmethylprednisolone. Other anti-inflammatory, analgesic or antipyreticagents that may be used include the nonselective COX inhibitors (e.g.,salicylic acid derivatives, aspirin, sodium salicylate, cholinemagnesium trisalicylate, salsalate, diflunisal, sulfasalazine andolsalazine; para-aminophenol derivatives such as acetaminophen; indoleand indene acetic acids such as indomethacin and sulindac; heteroarylacetic acids such as tolmetin, dicofenac and ketorolac; arylpropionicacids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofenand oxaprozin; anthranilic acids (fenamates) such as mefenamic acid andmeloxicam; enolic acids such as the oxicams (piroxicam, meloxicam) andalkanones such as nabumetone) and Selective COX-2 Inhibitors (e.g.,diaryl-substituted furanones such as rofecoxib; diaryl-substitutedpyrazoles such as celecoxib; indole acetic acids such as etodolac andsulfonanilides such as nimesulide)

Additionally or alternatively, in some applications, such as those whereit is desired to treat or prevent an allergic or immune response and/orcellular proliferation, the substances delivered in this invention mayinclude a) various cytokine inhibitors such as humanized anti-cytokineantibodies, anti-cytokine receptor antibodies, recombinant (new cellresulting from genetic recombination) antagonists, or soluble receptors;b) various leucotriene modifiers such as zafirlukast, montelukast andzileuton; c) immunoglobulin E (IgE) inhibitors such as Omalizumab (ananti-IgE monoclonal antibody formerly called rhu Mab-E25) and secretoryleukocyte protease inhibitor) and d) SYK Kinase inhibitoers such as anagent designated as “R-112” manufactured by Rigel Pharmaceuticals, Inc,or South San Francisco, Calif.

Additionally or alternatively, in some applications, such as those whereit is desired to shrink mucosal tissue, cause decongestion or effecthemostasis, the substances delivered in this invention may includevarious vasoconstrictors for decongestant and or hemostatic purposesincluding but not limited to pseudoephedrine, xylometazoline,oxymetazoline, phenylephrine, epinephrine, etc.

Additionally or alternatively, in some applications, such as those whereit is desired to facilitate the flow of mucous, the substances deliveredin this invention may include various mucolytics or other agents thatmodify the viscosity or consistency of mucous or mucoid secretions,including but not limited to acetylcysteine (Mucomyst™, Mucosil™) andguaifenesin.

In one particular embodiment, the substance delivered by this inventioncomprises a combination of an anti-inflammatory agent (e.g. a steroid oran NSAID) and a mucolytic agent.

Additionally or alternatively, in some applications such as those whereit is desired to prevent or deter histamine release, the substancesdelivered in this invention may include various mast cell stabilizers ordrugs which prevent the release of histamine such as cromolyn (e.g.,Nasal Chrom®) and nedocromil.

Additionally or alternatively, in some applications such as those whereit is desired to prevent or inhibit the effect of histamine, thesubstances delivered in this invention may include variousantihistamines such as azelastine (e.g., Astylin®), diphenhydramine,loratidine, etc.

Additionally or alternatively, in some embodiments such as those whereit is desired to dissolve, degrade, cut, break or remodel bone orcartilage, the substances delivered in this invention may includesubstances that weaken or modify bone and/or cartilage to facilitateother procedures of this invention wherein bone or cartilage isremodeled, reshaped, broken or removed. One example of such an agentwould be a calcium chelator such as EDTA that could be injected ordelivered in a substance delivery implant next to a region of bone thatis to be remodeled or modified. Another example would be a preparationconsisting of or containing bone degrading cells such as osteoclasts.Other examples would include various enzymes of material that may softenor break down components of bone or cartilage such as collagenase (CGN),trypsin, trypsin/EDTA, hyaluronidase, and tosyllysylchloromethane(TLCM).

Additionally or alternatively, in some applications, the substancesdelivered in this invention may include other classes of substances thatare used to treat rhinitis, nasal polyps, nasal inflammation, and otherdisorders of the ear, nose and throat including but not limited toanti-cholinergic agents that tend to dry up nasal secretions such asipratropium (Atrovent Nasal®), as well as other agents not listed here.

Additionally or alternatively, in some applications such as those whereit is desired to draw fluid from polyps or edematous tissue, thesubstances delivered in this invention may include locally or topicallyacting diuretics such as furosemide and/or hyperosmolar agents such assodium chloride gel or other salt preparations that draw water fromtissue or substances that directly or indirectly change the osmolarcontent of the mucous to cause more water to exit the tissue to shrinkthe polyps directly at their site.

Additionally or alternatively, in some applications such as thosewherein it is desired to treat a tumor or cancerous lesion, thesubstances delivered in this invention may include antitumor agents(e.g., cancer chemotherapeutic agents, biological response modifiers,vascularization inhibitors, hormone receptor blockers, cryotherapeuticagents or other agents that destroy or inhibit neoplasia ortumorigenesis) such as; alkylating agents or other agents which directlykill cancer cells by attacking their DNA (e.g., cyclophosphamide,isophosphamide), nitrosoureas or other agents which kill cancer cells byinhibiting changes necessary for cellular DNA repair (e.g., carmustine(BCNU) and lomustine (CCNU)), antimetabolites and other agents thatblock cancer cell growth by interfering with certain cell functions,usually DNA synthesis (e.g., 6 mercaptopurine and 5-fluorouracil (5FU),antitumor antibiotics and other compounds that act by binding orintercalating DNA and preventing RNA synthesis (e.g., doxorubicin,daunorubicin, epirubicin, idarubicin, mitomycin-C and bleomycin) plant(vinca) alkaloids and other anti-tumor agents derived from plants (e.g.,vincristine and vinblastine), steroid hormones, hormone inhibitors,hormone receptor antagonists and other agents which affect the growth ofhormone-responsive cancers (e.g., tamoxifen, herceptin, aromataseingibitors such as aminoglutethamide and formestane, trriazoleinhibitors such as letrozole and anastrazole, steroidal inhibitors suchas exemestane), antiangiogenic proteins, small molecules, gene therapiesand/or other agents that inhibit angiogenesis or vascularization oftumors (e.g., meth-1, meth-2, thalidomide), bevacizumab (Avastin),squalamine, endostatin, angiostatin, Angiozyme, AE-941 (Neovastat),CC-5013 (Revimid), medi-522 (Vitaxin), 2-methoxyestradiol (2ME2,Panzem), carboxyamidotriazole (CAI), combretastatin A4 prodrug (CA4P),SU6668, SU11248, BMS-275291, COL-3, EMD 121974, IMC-1C11, IM862,TNP-470, celecoxib (Celebrex), rofecoxib (Vioxx), interferon alpha,interleukin-12 (IL-12) or any of the compounds identified in ScienceVol. 289, Pages 1197-1201 (Aug. 17, 2000) which is expresslyincorporated herein by reference, biological response modifiers (e.g.,interferon, bacillus calmette-guerin (BCG), monoclonal antibodies,interluken 2, granulocyte colony stimulating factor (GCSF), etc.), PGDFreceptor antagonists, herceptin, asparaginase, busulphan, carboplatin,cisplatin, carmustine, cchlorambucil, cytarabine, dacarbazine,etoposide, flucarbazine, flurouracil, gemcitabine, hydroxyurea,ifosphamide, irinotecan, lomustine, melphalan, mercaptopurine,methotrexate, thioguanine, thiotepa, tomudex, topotecan, treosulfan,vinblastine, vincristine, mitoazitrone, oxaliplatin, procarbazine,streptocin, taxol, taxotere, analogs/congeners and derivatives of suchcompounds as well as other antitumor agents not listed here.

Additionally or alternatively, in some applications such as those whereit is desired to grow new cells or to modify existing cells, thesubstances delivered in this invention may include cells (mucosal cells,fibroblasts, stem cells or genetically engineered cells) as well asgenes and gene delivery vehicles like plasmids, adenoviral vectors ornaked DNA, mRNA, etc. injected with genes that code foranti-inflammatory substances, etc., and, as mentioned above, osteoclaststhat modify or soften bone when so desired, cells that participate in oreffect mucogenesis or ciliagenesis, etc.

Additionally or alternatively to being combined with a device and/or asubstance releasing modality, it may be ideal to position the device ina specific location upstream in the mucous flow path (i.e. frontal sinusor ethmoid cells). This could allow the deposition of fewer drugreleasing devices, and permit the “bathing” of all the downstreamtissues with the desired drug. This utilization of mucous as a carrierfor the drug may be ideal, especially since the concentrations for thedrug may be highest in regions where the mucous is retained; whereasnon-diseased regions with good mucous flow will be less affected by thedrug. This could be particularly useful in chronic sinusitis, or tumorswhere bringing the concentration of drug higher at those specific sitesmay have greater therapeutic benefit. In all such cases, local deliverywill permit these drugs to have much less systemic impact. Further, itmay be ideal to configure the composition of the drug or delivery systemsuch that it maintains a loose affinity to the mucous permitting it todistribute evenly in the flow. Also, in some applications, rather than adrug, a solute such as a salt or other mucous soluble material may bepositioned at a location whereby mucous will contact the substance and aquantity of the substance will become dissolved in the mucous therebychanging some property (e.g., pH, osmolarity, etc) of the mucous. Insome cases, this technique may be used to render the mucous hyperosmolarso that the flowing mucous will draw water and/or other fluid frompolyps, edematous mucosal tissue, etc., thereby providing a drying ordesiccating therapeutic effect.

Additionally or alternatively to substances directed towards localdelivery to affect changes within the sinus cavity, the nasal cavitiesprovide unique access to the olfactory system and thus the brain. Any ofthe devices and methods described herein may also be used to deliversubstances to the brain or alter the functioning of the olfactorysystem. Such examples include, the delivery of energy or the depositionof devices and/or substances and/or substance delivering implant(s) toocclude or alter olfactory perception, to suppress appetite or otherwisetreat obesity, epilepsy (e.g., barbiturates such as phenobarbital ormephoobarbital; iminostilbenes such as carbamazepine and oxcarbazepine;succinimides such as ethylsuximide; valproic acid; benzodiazepines suchas clonazepam, clorazepate, diazepam and lorazepam, gabapentin,lamotrigine, acetazolamide, felbamate, levetiraceam, tiagabine,topiramate, zonisamide, etc.), personality or mental disorders (e.g.,antidepressants, antianxiety agents, antipsychotics, etc.), chronicpain, Parkinson's disease (e.g., dopamine receptor agonists such asbromocriptine, pergolide, ropinitrol and pramipexole; dopamineprecursors such as levodopa; COMT inhibitors such as tolcapone andentacapone; selegiline; muscarinic receptor antagonists such astrihexyphenidyl, benztropine and diphenhydramine) and Alzheimer'sdisease, Huntington's disease or other dementias, disorders of cognitionor chronic degenerative diseases (e.g. tacrine, donepezil, rivastigmine,galantamine, fluoxetine, carbamazepine, clozapine, clonazepam andproteins or genetic therapies that inhibit the formation of beta-amyloidplaques), etc.

In certain applications, such as those intended for the treatment ofsinusitis or other disorders of the ear, nose or throat, the implantablesubstance delivery devices and methods of the present invention maysatisfy one or more of the following objectives:

1. Clearing of mucous: The implantable substance delivery devices ofthis invention may be configured such that, when implanted in a nasal orperinasal passageway, they will allow at least a portion of the adjacentanatomical wall(s) to maintain muco-ciliary action. To accomplish thisthe devices may have discrete areas which contact the adjacentanatomical wall(s) and other areas that do not contact the adjacentanatomical wall(s) and/or they may incorporate an internal hollow lumen.While some embodiments of the invention include a central lumen, in mostcases, it may be impossible or impracticable for mucous to flow throughthe lumen of the implanted device via gravity or sheer pressure. Thus,this central lumen may not be a usable structure to maintain patency ofthe anatomical passageway since in such cases fluids may more easily beconducted around the device. Accordingly, in other embodiments of thepresent invention as described herein, the device may comprise spacedapart struts or members which allow mucous to flow therebetween, thusavoiding any need for the mucous to enter a lumen or bore within thedevice. Also, there are other embodiments of the current invention wherethe struts are relatively thin and the device in composed of anopen-cellular structure such that the cilia are allowed to contact theinner lumen of the device directly. In these circumstance the clearingof mucous may be possible through the central lumen without relying onpressure or gravity.

2. Sustained Effect: Drug saturated gauze or sponges, as may be used todeliver drugs in some intranasal/intrasinus applications, have little orno ability to regulate the dosage(s) of drug(s) delivered or thedispersion of those drug(s). Further, they may be eithernon-biodegradable or very quickly biodegradable. At least someembodiments of the devices of the present invention overcome theseshortcomings by delivering predetermined dosages of drugs for apredetermined treatment duration and then, after conclusion of thepredetermined treatment duration, may be removed or may biodegrade andbe eliminated.

3. Minimally Invasive Placement: Many of the instruments currently usedto perform sinus procedures require significant obliteration of ordamage to tissues within the nose or sinus in order to gain access andplace implants. However, the devices and methods of the presentinvention may be carried out with minimal iatrogenic damage to nasal andsinus tissues. Thus, the devices and methods described herein may permitswollen tissues and obstructed lumens to be reduced through the actionof the drugs, and for infections to be controlled, thereby resulting ina resolution of symptoms without the need for invasive tissue-damagingtherapy such as traditional sinus surgery.

4. Low risk of device infection: In accordance with this invention,implantable substance delivery devices may be made of a material that isnaturally antiinfective or may be coated with such a material. This mayaid in avoidance of “toxic-shock” syndrome or other similar devicerelated infections. Alternatively they may be removable or resistant toinfection as a result of their mechanical structure or integrity.

5. Removable or biodegradable: In some embodiments, the implantablesubstance delivery devices of the present invention may be biodegradableand/or removable. In some applications, it will be desirable for thedevice to be biodegradable over a desired time period, yet be removableif conditions merit it's early removal (e.g., before sufficient time haselapsed to allow the device to fully biodegrade). To aid in theremovability of the structure a tail, or suture/string attachment pointmay be provided to permit easy removal in the office.

6. Ability to deliver one or more diagnostic or therapeutic substances:Since sinus disease has many etiologies, it would be ideal to allow thephysician to customize the device to contain one or more substances inorder to treat an individual patient's disorder. Alternatively, it mayalso be acceptable to have mixtures or combinations of substances (e.g.,a fixed dosage combination of two or more drugs) pre-packaged forloading into the implantable substance delivery device before or afterit has been implanted. Such prepackaged mixtures or combinations ofsubstances may be in liquid form suitable for direct loading into thedevice or may be in dry form (e.g., lyophilized or powder) that may beeasily reconstituted with a specified volume of liquid (e.g., sterilewater, 0.9% NaCl solution, etc.). Alternatively the device may containtwo or more separated chambers that simultaneously or sequentiallyrelease drug(s). Alternatively, one other embodiment may include one ormore drugs or substances that are pre-bound or pre-loaded within thedevice without being mixed with any additive or one or more drugs orsubstances may be added or mixed with other additives at the time ofuse.

7. Preventing scarring or adhesions: Any material placed in the sinusshould be designed of material such that adhesions or scarring may beminimized to allow for the continued patency of the channels in whichthey are placed. While simply having a mechanical barrier to adhesionmay be useful, it is also important that the implant itself does notinduce a tissue reaction. Inert materials should be used to avoid thiscondition. In other embodiments it may be necessary to release an agentcapable of preventing the tissue response to the implant. Nominally,although a vast array of therapeutic substances may be used inside thedevice, it may also have utility simply as a spacer to maintain thepassageway in which it is delivered, filled with an inert substance suchas saline.

8: Drug delivery kinetics: The devices of the present invention candeliver therapeutic substances in a consistent or predictable mannerover the course of the therapy, and if possible, this timing of deliverywould be programmable based upon the material chosen. In somecircumstances it may be ideal to allow the device to be refilled insitu, but in some embodiments the device may be capable of containingenough therapeutic substance so that refilling would not be necessary.To date there is no device proposed or available which can satisfy theseneeds and thus the need still exists for new devices and methods fordelivering drugs and other therapeutic or diagnostic substances intoparanasal sinuses or other locations within the body for the treatmentof sinusitis or other diseases and disorders.

Though the implantable substance delivery device may be delivered to orremoved from the sinuses or other regions in the ear, nose, or throatvia standard surgical techniques, it is of particular interest that thesubstance delivery device may also be delivered via minimally invasivemeans which may reduce bleeding, tissue removal, post-operative care,and other surgical issues.

A catheter, which may be malleable, deflectable, and/or have anappropriately shaped body and tip may be introduced into the nose andnear or into the location of interest, such as the ostia of a sinus. Thecatheter may or may not be introduced through an access port located inthe nostril. Furthermore, the guide may be positioned in the anatomy viasuch means, but not limited to: direct visualization, endoscopicimaging, fluoroscopic imaging, electromagnetic sensing, etc. Onceproperly positioned near or through the appropriate ostium, a guide wiremay be advanced through the catheter and into a sinus cavity. Forexample, in the case of accessing the Maxillary or Frontal sinus, thecatheter tip may curve around the uncinate process (without the need toresect the uncinate) and enter through or point toward the appropriatesinus ostia. A guide wire can than be advanced into the sinus cavity.These maneuvers may be done under fluoroscopic, endoscopic,electromagnetic sensing, etc. visualization methods. Appropriatelyshaped, deflectable, and/or malleable catheters may also be used to gainaccess to the frontal and sphenoidal sinuses. Once a wire is advancedinto the sinus, a balloon catheter may be introduced over the wire inorder to enlarge the ostia of the sinus in question if it is deemednecessary. If desired, a second catheter may be advanced over the wireand through the access catheter. This second catheter may be used toexchange for a smaller guide wire—thus allowing for the use of smallercatheters that are compatible with the smaller guide wire.

Access to the Sphenoid sinus may be accomplished similarly by advancingthe access catheter medial to the middle turbinate and placing thecatheter through or close to the ostium of the sinus. Similar techniquesof advancing a guide wire into the sinus with subsequent balloondilation prior to delivery of the substance delivery device may thenfollow.

Access to the Ethmoid sinuses may be accomplished similarly by advancingthe access catheter into or close to the retrobullar and suprabullarrecesses, which provide entry into the ethmoid cells. Similar techniquesof navigating and advancing a guide wire through and into the cells withsubsequent balloon dilation prior to delivery of the substance deliverydevice may then follow. Alternatively, it may be desirable to advance acatheter near the anterior ethmoid (e.g. Ethmoid Bulla) underfluoroscopic, endoscopic, electromagnetic sensing, etc.visualization/navigation. Subsequently, a piercing member such as aneedle or catheter may be advance through the access catheter, andthrough the walls of the anterior and posterior ethmoid cells. Once oneor more walls are pierced, a guidewire may be advanced into the ethmoidcells via the needle or other catheter member. Balloon dilation of thepierced anterior and posterior ethmoid cells may be conducted, ifdesired, prior to placement of the substance delivery device. Ingeneral, minimally invasive access to the sinuses and their surroundingareas is a key element to delivering a substance delivery device.

Turning now to FIGS. 1-12F, it is to be understood that such figuresshow specific examples of the devices and methods of the presentinvention. Any elements, attributes, components, accessories or featuresof one embodiment or example shown in these figures may be eliminatedfrom that embodiment or example, or may be included in any otherembodiment or example, unless to do so would render the resultantembodiment or example unusable for its intended purpose.

FIG. 1 generally shows a diagram of the head of a human patient whereina system 10 of the present invention is being employed to implant asubstance delivery device 12 of the present invention within the leftfrontal sinus. As shown, this system 10 comprises a nasal access portdevice 14, a delivery catheter 16, an elongate member 18 and theimplantable substance delivery device 12. The port device 14 ispositioned within the nostril, as shown. Examples of nasal port devicesthat may be useable are described in detail in parent application Ser.No. 10/829,917 entitled “Devices, Systems and Methods for Diagnosing andTreating Sinusitis and Other Disorders of the Ears, Nose and/or Throat,”which is incorporated herein by reference. The catheter 16 is advancedthrough the port device 14 and through the nasal cavity to a locationwithin or very near the ostium to the left frontal sinus. Prior to orafter insertion of the catheter 16, the implantable substance deliverydevice 12 is loaded into the lumen of the delivery catheter 16 and theelongate member 18 is positioned in the lumen of the delivery catheter16 proximal to the implantable substance delivery device 12. It will beappreciated that, in some cases, a separate guide catheter (not shown)may be advanced through port device 14 and to a position near the ostiumof the left frontal sinus and thereafter the delivery catheter may beadvanced through that guide catheter to a position where the distal endof the delivery catheter is in or immediately adjacent to the ostium ofthe left frontal sinus. Thereafter, the elongate member 18 may beadvanced in the distal direction thereby pushing the implantablesubstance delivery device 12 out of the distal end of the deliverycatheter 16. Alternatively, the distal end of the elongate member 18 maybe positioned in contact with the proximal end of the drug deliverydevice 12 within the lumen of the delivery catheter 16 and, thereafter,the elongate member 18 may be held stationary while the deliverycatheter 16 is retracted in the proximal direction so as to cause theimplantable substance delivery device 12 to pass out of the distal endof the delivery catheter 16. In either case, the substance deliverydevice 12 will be positioned fully or partially within the frontal sinusand, thereafter, the port device 14, delivery catheter 16 and elongatemember 18 may be removed. The implantable substance delivery device 12may be constructed in various ways, examples of which are shown in FIGS.2-12F and described herebelow. In any of the embodiments of thisinvention, the desired diagnostic or therapeutic substance may be loadedinto the implantable substace delivery device 12 before and/or after thedevice 12 has been inplanted within the body.

FIGS. 2-2C show one embodiment of an implantable substance deliverydevice 12 a which tube 20 having a lumen 22, a porous matrix 24 and anouter barrier 26. One end of the tube 20 protrudes through the outerbarrier 26 and has a needle-penetrable, self-sealing cap 27 thereon. Theother end of the tube 20 is closed such that the lumen 22 of the tubeforms a hollow cavity within the approximate center of the porous matrix24. A solution containing the desired therapeutic or diagnosticsubstance is introduced into the lumen 22 of the tube 20 by a syringeand needle 28, as shown in FIG. 2A. The tube 20 is constructed of porousor permeable material such as expanded polytetrafluoroethylene (ePTFE)or a bioabsorbable material such as porous poly (L-lactic acid) (PLLA)or poly(L-glycolic acid) (PLGA,) etc. which allows the substance to passthrough the wall of the tube 20 and into the porous matrix 24. In thismanner, the porous matrix 24 becomes substantially saturated or loadedwith the substance such that the lumen 22 of tube 20 and the porousmatrix 24 combine to form a reservoir in which a quantity of thesubstance is contained. The porous matrix may be formed of abiodegradable or non-biodegradable porous material such as a flexible orrigid polymer foam, cotton wadding, gauze, hydrogel, collagen etc.Examples of biodegradable polymers that may be foamed or otherwiserendered porous include poly(L-lactic acid) (PLLA), poly(L-glycolicacid) (PLGA), polyglycolide, poly-L-lactide, poly-D-lactide, poly(aminoacids), polydioxanone, polycaprolactone, polygluconate, polylacticacid-polyethylene oxide copolymers, modified cellulose, collagen,polyorthoesters, polyhydroxybutyrate, polyanhydride, polyphosphoester,poly(alpha-hydroxy acid) and combinations thereof. This device 12 a maybe fully or partially biodegradable or non-biodegradable. Innon-biodegradable embodiments of the device 12 a, the tube 20, porousbody 24 and outer barrier 26 The tube 20 may be formed of any suitablematerial, such as various commercially available biocompatible polymersincluding but not limited to silicone rubber, polyethyleneterephthalate, ultra high molecular weight polyethylene, expandedpolytetrafloroethylene, polypropylene, polycarbonate urethane,polyurethane, polyamides.

Any embodiment of this invention, such as that shown in FIG. 2-2B, couldincorporate a means for assisting the transport of a substance acrossthe barrier. Such a device could take the form of a mechanical pump, anelectromechanical pump, a nanotechnology pumping mechanism, or anelectrical device that emits a current to drive the transport. Thismeans could be incorporated into the barrier itself or into the porousmatrix. A more specific example of a mechanical embodiment would be tomechanically change the reservoir size so that the volume of substanceto be delivered is continually under positive pressure to drive itstransport across the barrier. This mechanical change could be controlledvia micro-electronics and could be pre-programmed or remotely controlledthrough various wireless communication technologies. Another example ofa mechanical means to maintain pressure within the reservoir would be toincorporate a membrane barrier that contracts or shrinks as the drugvolume diminishes such as an osmotic pump, or one activated by aninternal chemical reaction. This contraction could be achieved bycreating the membrane barrier from an elastic or shrinking polymer or byincluding movable filaments or sections that decrease the reservoirvolume.

In any embodiment of this invention, the wall of any tube 22 or othercavity formed within or next to the porous matrix 24 may be constructedof material that controls the rate at which the substance passes fromthe lumen 22 of the tube 20 into the porous matrix 24. Also, the outerbarrier 26 may be constructed of material (e.g., a semi-permeablemembrane or film) which will control the rate at which the substancewill pass from the porous matrix 24 through the outer barrier 26 and outof the device 12. There may be other embodiments of the substancedelivery device that utilize multiple chambers within the device tocontain multiple drugs. These chambers could be arranged in variousconfigurations, including, but not limited to being arranged axially sothat a strip of each chamber travels the length of the device but thecross-section shows multiple compartments, longitudinally so that thedistal portion of the device could contain a different drug than themiddle or proximal portions, or in layers (like an onion) such that thefirst drug that gets delivered may be different than the next drug totreat various afflictions at different times—i.e. first addressinginflammation, then after a predetermined period to begin releasingantimicrobials to combat infection. In the layered configuration, thedividing membranes may or may not be biodegradable. The device 12 ofthis invention may initially be provided without diagnostic ortherapeutic substance contained in the device 12. In such cases, aphysician may then select or formulate a particular therapeutic ordiagnostic substance or combination of such substances into the device12 before the device is implanted in the subject's body. In otherapplications, the physician may load a desired therapeutic or diagnosticsubstance or combination of such substances into the device 12 after thedevice has been implanted in the subject's body. To facilitate thephysician's selection or formulation of the diagnostic or therapeuticsubstance(s) to be loaded into the device 12, the device may beaccompanied by a data compilation for facilitating dilution ofsubstance(s) and loading of the devices 12 such that desired dosage(s)of the substance(s) that have been loaded into the device 12 will bedelivered by the implanted device 12. Such data compilation may be inthe form of tabular data, algorhythm(s) etc. Also, such data compilationmay be provided in written form (e.g., as a table or list) as hard copy(e.g., a package insert or booklet) or stored in electronic form (e.g.,on compact disc, accessible from a website, programmed into a computeror microprocessor device such as a hand held electronic dosagecalculator that is programmed specifically for use in conjunction withthe devices 12 of the present invention). The dosage of particularsubstance(s) delivered by the devices 12 will be determined rate(s) atwhich certain substances, preparations, mixtures or concentrations ofsolutes or substances having certain defined key properties will passthrough the barriers 26 of the devices 12. The data compilation mayinclude or comprise examples or lists of certain key properties forwhich specific barrier transition rates may be provided include aviscosity or a range of viscosities, molecular weight or range ofmolecular weights, an electrical charge, osmolarity or a range ofosmolarities, osmolality or a range of osmolalities, presence of acertain chemical group or atom, relative hydrophilicity and/orhydrophobic properties, etc. An example of one type of data compilationthat may be provided to facilitate preparation and loading of a device12 of the present invention with specific steroid orsteroid/antimicrobial formulations is a tabular presentation as shown inTable 1 below:

TABLE 1 Concentration of Drug or Drug Combination in Solution (mg ofdrug or drug Diffusion Rate Out of Device (Drug or Drug Combination perml of (amount of each drug delivered Combination / Solvent) solution)per 24 hour period) fluticasone proprionate X mg/ml 200 mcg fluticasoneproprionate/24 hr (as microfine aqueous Y mg/ml 230 mcg fluticasoneproprionate/24 hr suspension) Z mg/ml 260 mcg fluticasone proprionate/24hr cefuroxime axetil + X mg/ml 200 mcg fluticasone proprionate + 8fluticasone proprionate mg cefuroxime axetil/24 hr in 0.9% saline Ymg/ml 230 mcg fluticasone proprionate + 12 mg cefuroxime axetil/24 hr Zmg/ml 260 mcg fluticasone proprionate + 20 mg cefuroxime axetil/24 hrtriamcinolone acetonide X mg/ml 180 mcg triamcinolone cetonide/24 hr (asaqueous Y mg/ml 220 mcg triamcinolone cetonide/24 hr microcrystalline Zmg/ml 260 mcg triamcinoione cetonide/24 hr suspension). amoxicillin +clavulanate + X mg/ml 180 mcg triamcinolone cetonide + 40 _triamcinolonemcg amoxicilin + 20 mcg acetonide in 0.9% saline clavulanate/24 hr assolution/aqueous Y mg/ml 220 mcg triamcinolone cetonide microcrystallinecetonide + 60 mcg amoxicilin + 40 suspension mcg clavulanate/24 hr Zmg/ml 260 mcg triamcinolone cetonide cetonide + 80 mcg amoxicilin + 60mg clavulanate/24 hr clotrimazole + X mg/ml 170 mcg clotrimazole + 100mcg betamethasone betamethasone dipropionate/24 hr dipropionate in Ymg/ml 200 mcg clotrimazole + 125 mcg polyethylene glycol betamethasonedipropionate/24 hr Z mg/ml 125 mcg clotrimazole + 150 mcg betamethasonedipropionate/24 hr mupirocin calcium X mg/ml 1 mg mupirocin calcium/24hr Y mg/ml 4 mg mupirocin calcium/24 hr Z mg/ml 8 mg mupirocincalcium/24 hr mupirocin calcium + X mg/ml 1 mg mupirocin calcium + 200mcg fluticasone proprionate fluticasone proprionate/24 hr (assolution/microfine Y mg/ml 4 mg mupirocin calcium + 220 mcg aqueoussuspension) triamcinolone cetonide/24 hr Z mg/ml 8 mg mupirocincalcium + 260 mcg fluticasone proprionate/24 hr

All percentages set forth in this table are expressed as percent byweight. It is to be appreciated that this table is merely anillustrative example provided to show one way in which instructionalinformation or data on substance release rates that may accompanycertain implantable substance delivery devices 12 of the presentinvention to facilitate their loading and use with different substancesand/or differing concentrations of substances. The actual substancesused and actual delivery rates of those substances will depend on theintended use of the device 12, the key properties of the substance to beloaded into the device 12 and the relative porosity or permeability ofthe porous matrix 24 and/or outer barrier 26 of the device 12. Theabove-set-forth table shows several examples whereby a physician may usea starting preparation that contains one or more drugs (e.g., thepreparations listed in the left column) to prepare different dilutions(e.g., concentrations X, Y or Z listed in the middle column) which willdeliver different topical doses of the agents contained in thepreparation (e.g., the daily dosages listed in the right column). Thestarting preparation (e.g., the preparations listed in the left column)may comprise a commercially available pharmaceutical preparation that isapproved and/or useable for intranasal administration or topicaladministration to mucosal tissues elsewhere in the body. The startingpreparation (e.g., the preparations listed in the left column) may be a)packaged and/or provided along with the devices 12 of the presentinvention, b) obtained by the physician separately from the devices 12of the present invention and/or c) pre-loaded in concentrated (e.g., dryor lyophilized form) within the devices 12 of the present invention, asdescribed herein. In some cases, the devices 12 may be provided with adry (e.g, lyophilized or powdered) diagnostic or therapeutic substance(e.g., a drug preparation) contained in the device (e.g. within thelumen 22 of the tube 20 and/or within the porous matrix 24) and thephysician may subsequently inject a measured amount of a solvent (e.g.,sterile water, 0.9% NaCl solution, basic salt solution, etc.) toreconstitute or dissolve the substance and to expand or activate thedevice 12. In such cases, the instructions or other information providedwith the device 12 may include information for different concentrationsof substance produced by injecting different amounts of solvent. Inother cases, the devices may be provided in an expanded state and needto be compressed or re-shaped for delivery then re-expanded fully,slightly, or not at all depending upon the desired implantationlocation. As stated above, in some cases, the starting preparation(e.g., the preparations listed in the left column) may be commerciallyavailable preparations. For example, fluticasone proprionate referred toin the first 1, 2 and 7 of Table 1 is commercially available as apreparation for intranasal spray administration as Flonase® nasal spray(Glaxo-SmithKline, Research Triangle Park, N.C.). Fluticasonepropionate, the active component of Flonase® nasal spray, is a syntheticcorticosteroid having the chemical nameS-(fluoromethyl)6<,9-difluoro-11®-17-dihydroxy-16<-methyl-3-oxoandrosta-1,4-diene-17®-carbothioate,17-propionate.It is provided as an an aqueous suspension of microfine fluticasonepropionate containg microcrystalline cellulose andcarboxymethylcellulosesodium, dextrose, 0.02% w/w benzalkonium chloride,polysorbate 80, and 0.25% w/w phenylethyl alcohol, and having a pHbetween 5 and 7. This commercially available Flonase product may, insome cases, serve as the base preparation (left column of Table 1) whichmay be combined with one or more other substances and/or prepared invarious dilutions (e.g., middle column of Table 1) prior to being loadedinto the device 12 such that the device 12 will, when subsequentlyimplanted in the subject's body, deliver a desired dosahe of fluticasonepropionate alone or in combination with other agent(s) (right column ofTable 1). In instances such as this where the substance is in the formof a suspension, the suspension may be formulated such that it willremain stable within the implanted device 12 and the barrier 26 of thedevice 12 may comprise a membrane that has pores which are large enoughto allow the particles (e.g., microparticles) of the suspension to passthrough the barrier at the desired rate.

Similarly, triamcinolone acetonide referred to in rows 3 and 4 of Table1 is commercially available as Nasacort® AQ nasal spray (AventisPharmaceuticals, Inc., Bridgewater, N.J.). Triamcinolone acetonide, theactive ingredient in Nasacort® AQ nasal spray, is9-Fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic16,17-acetal with acetone (C₂₄H₃₁FO₆). It is provided as amicrocrystalline suspension of triamcinolone acetonide in an aqueousmedium with microcrystalline cellulose, carboxymethylcellulose sodium,polysorbate 80, dextrose, benzalkonium chloride, and edetate disodium.Hydrochloric acid or sodium hydroxide may be added to adjust the pH to atarget of 5.0 within a range of 4.5 and 6.0.

Also, preparations of the antifungal agent clotrimazole combined withthe corticosteroid betamethasone dipropionate as referred to in row 5 ofTable 1 are commercially available as Lotrisone® lotion (ScheringCorporation, Kenilworth, N.J.) for topical application to treat fungalinfections. Chemically, clotrimazole is1-(a-Chloro,a,a-diphenylbenzyl)imid-azole, with the empirical formulaC₂₂H₁₇CIN₂ and a molecular weight of 344.8. Clotrimazole is an odorless,white crystalline powder, insoluble in water and soluble in ethanol.Betamethasone dipropionate has the chemical name9-Fluoro-1,16,17,21-trihydroxy-16B-methylpregna-1,4-diene-3,20-dione-17,21-dipropionate,with the empirical formula C₂₈H₃₇FO₇ and a molecular weight of 504.6.Betamethasone dipropionate is a white to creamy white, odorlesscrystalline powder, insoluble in water. Each gram of Lotrisone® lotioncontains 10 mg clotrimazole and 0.643 mg betamethasone dipropionate(equivalent to 0.5 mg betamethasone), in a hydrophilic base of purifiedwater, mineral oil, white petrolatum, cetyl alcohol plus stearylalcohol, ceteareth-30, propylene glycol, sodium phosphate monobasicmonohydrate, and phosphoric acid; benzyl alcohol as a preservative. Forapplications where the device 12 of the present invention is to beimplanted in the nose, paranasal sinus or other location within the ear,nose or throat, the base preparation (left column of Table 1) maycomprise low-viscosity forms of the Lotrisone® lotion or may comprise asolution or suspension of microparticles containing the activeingredients of Lotrisone® lotion absent the lotion base (e.g, excludingsome or all of the mineral oil, white petrolatum, cetyl alcohol plusstearyl alcohol, ceteareth-30 and/or propylene glycol).

Also, mupirocin calcium is an antibiotic that is commercially availableas Bactroban Nasal® ointment (Glaxo-SmithKline, Research Triangle Park,N.C.) for intranasal application. Bactroban Nasal® ointment contains2.15% w/w mupirocin calcium (equivalent to 2.0% pure mupirocin freeacid) in a soft white ointment base that contains paraffin and a mixtureof glycerin esters (Softisan® 649). The Mupirocin calcium is in the formof the dihydrate crystalline calcium hemi-salt of mupirocin. Chemically,it is (aE,2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-Epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-β-methyl-2H-pyran-2-crotonicacid, ester with 9-hydroxynonanoic acid, calcium salt (2:1), dihydrate.The molecular formula of mupirocin calcium is (C26H43O9)2Ca.2H2O, andthe molecular weight is 1075.3. The molecular weight of mupirocin freeacid is 500.6. For applications where the device 12 of the presentinvention is to be implanted in the nose, paranasal sinus or otherlocation within the ear, nose or throat, the base preparation (leftcolumn of Table 1) may comprise low-viscosity forms of the BactrobanNasal® ointment or may comprise a solution or suspension ofmicroparticles containing the active ingredients of Bactroban Nasal®ointment absent the ointment base (e.g, excluding some or all of theparaffin andor glycerin esters (Softisan® 649)).

FIG. 2B shows a variant of the implantable substance delivery device 12b comprising the same components as the device 12 a of FIGS. 2 and 2Abut, instead of the needle-penetrable, self-sealing cap 27, this device12 b has a fill tube 32 connected to the exposed end of the inner tube22 by way of a removable connector 30. A check valve 31 may bepositioned in the lumen 22 just inside of the connector 30. This checkvalve may be a device or may simply be the function resulting from theelasticity of the materials chosen for its construction. A syringe orother substance injecting or infusing apparatus may be connected to thefree end of the fill tube 32 and a diagnostic or therapeutic substancecomprising or consisting of a fluid may be introduced through the filltube 32, through check valve 31 and into the reservoir (i.e., in thisembodiment the “reservoir” includes the lumen 22 as well as the adjacentporous matrix 24). Thereafter, the connector cap 30 and fill tube 32 maybe removed. Check valve 31 will prevent the substance from backflowingout of the protruding end of the inner tube 20. Alternatively, the filltube 32 may remain connected to the device 12 and may be closed (e.g.,compressed, clamped, clipped, sealed, cut, doubled over, ligated orotherwise manipulated or sealed as shown in the examples of FIGS. 8A-8Eand described herebelow).

The outer barrier controls the rate at which the diagnostic ortherapeutic substance will diffuse or pass out of the device 12 a or 12b. In some applications of the invention, the device 12 a or 12 b may beprovided to a physician in an empty state (i.e., without diagnostic ortherapeutic substance contained in lumen 22 or porous matrix 24). Thephysician may then select or self-formulate one or more diagnostic ortherapeutic substances to be loaded into the device 12 a, 12 b before orafter the device 12 a, 12 b has been implanted in the body.

FIG. 2C shows a general example where this implantable substancedelivery device 12, 12 a, 12 b is implanted within the ostium OS of aparanasal sinus PS such that a portion of the device 12, 12 a, 12 bextends into the paranasal sinus PS. In such cases where the device 12,12 a or 12 b is implanted in a paranasal sinus PS to treat sinusitis,the physician may load the lumen 22 and porous matrix 24 with any drugsor other diagnostic or therapeutic substance that he or she deemssuitable for treatment of the condition. For example, the device 12, 12a, 12 b may be loaded with a corticosteroid, such as one or more ofthose corticosteroids listed hereabove that have been approved forintranasal use (e.g., approved for topical application as a nasal sprayor for intramucosal injection directly into the nasal turbinates ornasal mucosa). One specific example is an aqueous solution ofFluticasone Proprionate (Flonase, Glaxo-SmithKline). For intranasal orparanasal applications, the empty device 12 b shown in FIG. 2A may beinitially delivered and positioned within the paranasal sinus PS and thefill tube 32 may extend into the nasal cavity or out of the subjectsnostril. The physician may then infuse the desired substance through thefill tube 32 and into the device 12 b. After the lumen 22 and porousmatrix 24 have been loaded with the desired amount of substance, theconnector 30 may be disconnected and the fill tube 32 removed or,alternatively, the fill tube may be allowed to remain attached to thedevice 12 b to facilitation subsequent in situ refilling of the device12 b. In one embodiment, the fill tube is connected to a subcutaneoussubstance reservoir. The subcutaneous substance reservoir may comprise apumping mechanism and is especially useful for chronic delivery of thesubstance. The subcutaneous drug reservoir may be refillable.

FIGS. 3-4C show additional embodiments of implantable substance deliverydevices 12 c and 12 d. Like the embodiments 12 a and 12 b shown in FIGS.2-2 c, these embodiments 12 c, 12 d comprise at least a porous matrix 24and an outer barrier 26, as described above. Optionally, theseembodiments 12 c, 12 d may also have an inner tube 20 or other hollowcavity formed within or next to the porous matrix 24. The outer surfacesof these devices 12 c, 12 d are shaped to define peaks 34 and valleys36. When the device 12 c, 12 d is implanted in the body of a subject andloaded with the desired diagnostic or therapeutic substance, the peaks34 will contact adjacent anatomical tissue and valleys 36 will remain aspaced distance away from adjacent anatomical tissue. In this manner,the surface to surface contact of the device is minimized and normalflow of body fluids and/or function of anatomical tissues may continuein the areas adjacent to the valleys 36 of the device 12 c, 12 d. Forexample, in cases where the device 12 c, 12 d is placed within a nasalcavity, paranasal sinus, Eustachian tube, nasolacrimal duct or otherpassageway lined with ciliated mucosa, the peaks 34 will make firmabutting contact the mucosal tissue thereby holding the device 12 c, 12d in place but the valleys 36 will remain a spaced distance away fromthe mucosal tissue so as not to substantially interfere with mucocillarytransport by that tissue or mucous flow past the implanted device 12 c,12 d.

In the examples of FIGS. 3 and 4, the implantable substance deliverydevices 12 c, 12 d have a fill tube 38 that is connected to the device12 c, 12 d. In embodiments where there is no hollow cavity or tube 20within the porous matrix 24, the diagnostic or therapeutic substance maybe infused through the tube 38 such that it will be absorbed into porousmatrix 24 and no closure or the tube or check valve will then berequired as the substance will substantially remain within the porousmatrix 24. However, in embodiments where the device 12 c, 12 d does havea hollow cavity (e.g., a tube 20 as shown in FIGS. 2-2B) within or nextto the porous matrix 24, there may be a check valve or other means forclosing the tube 38 (e.g., compressing, clamping, clipping, sealing,cutting, doubling over, ligating or otherwise manipulating or sealingthe tube as shown in the examples of FIGS. 8A-8E and describedherebelow) to prevent the substance from backflowing from the hollowcavity through the tube 38.

FIGS. 4-4C show an embodiment of the implantable substance deliverydevice 12 d that further comprises a frame 40. Such frame may impartstructural rigidity or a specific shape to all or any portion of thedevice 12 d. Alternatively or additionally, such frame may act as ascaffold or support structure and/or may be self-expanding orpressure-expandable so as to exert outwardly directed force against anadjacent anatomical tissue or structure. Although FIG. 4 shows a frame40 that extends over the entire length of the device 12 d, it is to beappreciated that the frame 40 may be confined to one or more specificregion(s) of any device 12, such as in the example of FIGS. 12D-12Edescribed herebelow. The frame 40 may be formed of any suitablematerial, including but not limited to wire, mesh, polymer, etc. In theparticular example shown in FIGS. 4-4B, the frame 40 comprises aself-expanding stent formed of wire members 42. In some embodiments, thewire members 42 may be positioned on the outer surface of the porousmatrix 24 within or inside of the outer barrier 26, as shown in FIG.4BA. Such embodiments may be manufactured by initially placing theporous matrix 24 (e.g. a sponge or mass of absorptive material) withinthe frame 40 and then dipping, spray-applying, applying by lay-up of afilm or otherwise applying a polymer to from the outer barrier 26encapsulating the porous matrix 24 and the frame 40, as shown in FIG.4B. Alternatively, such embodiments may be manufactured by forming(e.g., foaming in place) the porous matrix 24 about the frame 40 suchthat some or all of the frame members 42 are embedded within the porousmatrix 24 as shown in FIG. 4C. The outer barrier 26 may then be placedor formed (e.g., dip coated, sprayed on, applied by lay-up of a film,etc.) on the outer surface of the porous matrix 24 as further shown inFIG. 4C. Also, another method of forming the device may include theinitial creation of the barrier film within a mold cavity, andsubsequently forming the foam within the film covered mold cavity.

In one embodiment, the device 12 d comprises multiple, substantiallynon-intersecting ridges on its outer surface. The ridges enable only aportion of the device 12 d to contact adjacent anatomical tissue whilekeeping bulk of the device 12 d spaced a distance away from adjacentanatomical tissue. The ridges are designed to be substantially parallelto the direction of flow of fluids (e.g. mucous) along the walls of theadjacent anatomical tissue. This design enables reduced interfere withmucociliary transport by that tissue or the flow of fluids (e.g. mucous)past the device 12 d.

Some embodiments of the implantable substance delivery devices 12 of thepresent invention may be configured to define at lest one lumen of flowchannel through which body fluid or extraneously introduced fluid mayflow after the device 12 has been implanted in a natural or man madepassageway of the body. Examples of this concept include devices 12 c,12 d having peaks 34 and valleys 36 as shown in FIGS. 3 and 4, as wellas 12 e and 12 f having other flow-facilitating configurations, examplesof which are shown in FIGS. 5-6. The device 12 e of FIGS. 5 and 5Acomprises a porous matrix 24 covered with an outer barrier 26 and is inthe shape of a helical strip (e.g., the shape of a screw or auger). Whenloaded with the desired diagnostic or therapeutic substance andimplanted in a body lumen or passageway, this device 12 e defines ahelical groove or flowpath 50 through which fluid (e.g., mucous, bodyfluid, etc.) may flow. The device 12 e of FIG. 5 also incorporates anoptional grasping member 52 to facilitate grasping of the device 12 e byforceps, by hand or by other instruments while removing, moving ormanipulating the device 12 e. In the particular example shown, thegrasping member 52 comprises a strand of suture thread that extends fromone end of the device 52 but it is to be appreciated that such graspingmember 52 may be of any suitable design or construction and may belocated over the entire length of the device. For example, small threadsor projections, a net or other graspable structure may be located atnumerous location on the outer surface of the device so as to facilitatemoving or removing the entire device or portion(s) of the device afterthe device has begun to break apart or biodegrade in situ.

FIG. 6A shows an implantable substance delivery device 12 f of thepresent invention that comprises a helical substance eluting filament.This helical structure defines a hollow lumen 54 through the center ofthe device 12 f and open spaces 56 between individual convolutions ofthe helix, through which fluids (e.g., mucous or other body fluids) mayflow. This helical filament may be formed of any suitable biodegradableor nonbiodegradable material. Examples of biodegradable polymers thatmay be used to form the filament include include poly(L-lactic acid)(PLLA), poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide,poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxide copolymers, modifiedcellulose, collagen, polyorthoesters, polyhydroxybutyrate,polyanhydride, polyphosphoester, poly(alpha-hydroxy acid) andcombinations thereof. This filament may contain or may be coated withthe diagnostic or therapeutic substance or a preparation that containsthe diagnostic or therapeutic substance such that the substance willelute from the filament after the filament has been implanted in thebody.

FIGS. 6B-6D show In another embodiment of an implantable substancedelivering device 12 m which comprises a plurality of substance elutingstruts 55 and may optionally include a spacing member 53. When thedevice 12 m is implanted, such as in the examples of FIGS. 6C and 6D,the struts 55 may be substantially parallel to the direction of flow offluids (e.g. mucous) along the walls of the adjacent anatomical tissue(e.g., a paranasal sinus, sinus ostium, intranasal meatus, etc.) Thisdesign enables reduced interference with the transport of fluids (e.g.mucociliary transport) along the walls of the adjacent anatomical tissueand in the spaces 57 between the struts 55. The device 12 m can beplaced both in anatomical cavities (e.g. nasal sinus cavities) and inanatomical passages (e.g. trachea, blood vessels etc.). The device 12 mhas a configuration that enables the struts 55 to substantially comeinto direct contact with the flow of fluids (e.g. mucous) past thestent. The device 12 m may be delivered to the intended implantationsite while in a collapsed configuration and may subsequently expand toan expanded configuration, as shown in the figures. This device 12 m maybe self expanding or pressure expandable (e.g., by inflation of aballoon within the collapsed device). The thickness of the struts 55 mayvary along the length of the device 12 m as shown in the example of FIG.6D. In such embodiments, the diagnostic or therapeutic substance may becontained in and eluted from the thicker in regions 51 of the struts 55and such substance may subsequently be carried or distributed by anatural flow of body fluid (e.g., mucos flow out of the paranasalsinus). Also, in such embodiments, the thinner regions of the struts 55may be located near the drainage openings of the anatomical tissue (e.g.ostia of a nasal sinus) to minimize obstruction to fluid drainage. Thedevice 12 m may comprise a spacing member 53, such as a tubular orcylindrical hub, and such spacing member 53 may be positionable in anopening of the anatomical tissue (e.g. ostium of a nasal sinus as shownin FIG. 6D). The spacing member 53 may or may not have drug elutingproperties. The spacing member 53 may be configured to perform ascaffolding function such as to deter narrowing of a man made or naturalan anatomical opening or passage in which it is positioned to ensurethat fluid flow through the opening is not compromised. The device 12 mmay be biodegradable or bioabsorbable.

FIGS. 7-7B show an example of an implantable substance delivery device12 g of the present invention that is designed to be implanted andsubsequently retained within a paranasal sinus. This device 12 g mayinclude the inner tube 20, porous matrix 24 and outer barrier 26 asshown in FIGS. 2 and 2A and described above. Additionally, thisembodiment of the device 12 g has an intrasinus portion 56 intended tobe positioned within the paranasal sinus, an intraostial portion 58intended to be positioned within the sinus ostium OS and an intranasalportion 60 intended to protrude into the nasal cavity. A fill tube 62having a needle-penetrable, self-sealing cap 64 is positioned on the endof the fill tube. It will be appreciated from the foregoing discussion,however, that various other fill site/closure apparatus or designs maybe used in place of this fill tube and cap arrangement 62, 64. Theintraostial portion 58 of device 12 g has an annular groove formedtherein. As may be appreciated from FIGS. 7A and 7B this annular grooveis configured to receive the annulus of the ostium OS and frictionallyengage the underlying bone B, thereby helping to position or seat and/orhold the device 12 g in its intended implantation position. Initially,the device 12 g is in a collapsed configuration wherein the device has adiameter or maximum cross dimension D1 that is small enough to beadvanced through the ostium OS and into the paranasal sinus, as shown inFIGS. 7. and 7A Thereafter, a syringe and needle 66 are used to inject aknown volume of a solution containing the desired diagnostic ortherapeutic substance 68 into the device 12 g. The loading of thesubstance containing solution into the device 12 g causes the intrasinusportion 56 to swell to a larger diameter D2, which is too large to passthrough the ostium OS, thereby tending to retain the intrasinus portion56 within the paranasal sinus, as shown in FIG. 7B.

FIGS. 8A-8E show several non-limiting examples of the manner in whichthe implantable substance delivery devices 12 of this invention may besealed or closed to prevent substantial backflow of the diagnostic ortherapeutic substance from the device 12 after the device 12 has beenloaded with substance.

In the embodiment of FIG. 8A, the device has a long fill tube 70 and aone way check valve 72 within the neck of the fill tube, immediatelyadjacent to the body of the device. After the device has been implantedand the substance has been infused through the fill tube into thedevice, the fill tube 70 may be cut to a desired length such that itwill not protrude from the subject's body or interfere with thesubject's daily activities.

FIG. 8B shows a device that has a fill tube 70 and a clip 74 which isuseable to clip the fill tube 70 to prevent substance from backflowingout of the fill tube 70.

FIG. 8C shows a device that has a fill tube 70 and a ligature 76, suchas a length of suture material or draw string which is useable to ligatethe fill tube 70 to prevent substance from backflowing out of the filltube 70. An annular indentation or groove may optionally be formed inthe fill tube to receive and prevent longitudinal slippage of theligature 76.

FIG. 8D shows a device that has a fill port 78 through which thesubstance is injected or otherwise loaded into device and an adhesiveapplicator 80 that may be used to apply an adhesive to the fill port 78thereby sealing the fill port 78 such that substance will not backflowout of the fill port 78.

FIG. 8E shows a device that has a fill tube 70 that is doubled over anda clamp 82 that is useable to clamp the doubled over fill tube 70 toprevent substance from backflowing out of the fill tube 70.

FIGS. 9-9B are directed to another embodiment of an implantablesubstance delivery device 12 h of the present invention. This device 12h comprises a container portion which comprises a container body 90 anda lid 92. The interior of the container portion is loaded with a desireddiagnostic or therapeutic substance. The lid 92 has a permeable barrier94 which allows the diagnostic or therapeutic substance to pass throughthe barrier 94 at approximately a known rate as described hereabove. Anattachment portion 98 attaches the container portion to bone and/or softtissue. Such attachment portion 98 may comprise any suitable type ofattachment apparatus or substance such as an adhesive, barb(s), a screw,a suture or stitch, a clip, a suction apparatus, a stent, aself-expanding portion that grip the walls of the anatomical target etc.As shown in FIG. 9A, the device 12 h may be mounted on a deliverycatheter 100 which is useable to deliver the device 12 h to its intendedimplantation location. In the example shown, the delivery catheter 100has engagement members 102 that engage projections 96, 98 on the device12 h, as shown, to hold the device 12 h on the end of the deliverycatheter as it is advanced into the body to the desired implantationlocation. The proximal end of the delivery catheter 100 comprises ahandpiece having a control knob 104. When the control knob 104 isretracted, the engagement members 102 will disengage the projections 96,98, thereby releasing the device 12 h and allowing the delivery catheter100 to be retracted and removed as shown in FIG. 9B. In cases where theattachment portion 98 comprises a screw, the delivery catheter 100 maybe braided or otherwise constructed in accordance with techniques wellknown in the art such that the catheter may be rotated to screw thescrew into adjacent soft tissue or bone, before the device 12 h isreleased from the delivery catheter 100. As in other embodimentsdiscussed above, the substance may be loaded into this device 12 hbefore or after the device 12 h has been implanted within the subject'sbody.

In one embodiment, the device 12 h is implanted in an anatomicallocation having a mucous flow in such a way that the eluted drug isdistributed to a wider region by the mucous flow. This is especiallyhelpful in the enhancing the efficacy of agents like mucolytics as theywould accumulate at higher concentrations in regions of higher mucousdensity. This also enables the reduction in size of the substancedelivery mechanism since it can be limited to deliver substances only toparticular regions from where the drug can be distributed mostefficiently.

FIGS. 10A and 10B show a system 110 for delivering another implantablesubstance delivery device which comprises a substance eluting filament12 j. This system 110 comprises the substance eluting filament 12 j, acatheter 114, a pusher 116 and a connector 118. The substance elutingfilament 12 j is advanced into the lumen of the delivery catheter 114.The pusher 116 is advanced into the lumen of the delivery catheter 114behind the substance eluting filament 12 j and the connector 118 isconnected to the proximal end of the delivery catheter 114. As shown inFIG. 10B, the delivery catheter 114 may then be advanced into thesubject's body to a position where the distal end of the deliverycatheter is within or near the location where the substance deliverydevice 12 j is to be implanted (e.g., within or near the ostium of aparanasal sinus). Thereafter the pusher may be advanced in the distaldirection or the pusher may be held stationary and the catheter 114 maybe retracted in the proximal direction to push the substance deliverydevice 12 j out of the end of distal end of the catheter and into thedesired implantation site (e.g., paranasal sinus). The substance elutingfilament may or may not be biased to a specific shape or coiledconfiguration. In one embodiment, the substance eluting filament 12 jassumes a random coiled shape within the implant location.

The implantable substance delivery devices 12 of this invention and/orthe delivery catheter or delivery devices used to deliver such devices12 into the body may, in some instances, be configured for over-the-wireor rapid exchange delivery. FIG. 11A shows an illustrative example of arapid exchange embodiment of this invention and FIG. 11B shows anillustrative example of an over-the-wire embodiment. In the rapidexchange embodiment shown in FIG. 11A, the delivery catheter 120 has afirst lumen within which the implantable substance delivery device 12 kand elongate delivery member or pusher 126 are positioned. A side tube124 having a second lumen 122 is located on a side of the deliverycatheter 120, as shown. Thus, a guidewire GW may pass through the sidelumen 122, thereby allowing the system to be advanced over a previouslyinserted guidewire.

FIG. 11B shows an over-the-wire embodiment comprising a deliverycatheter 130 having a lumen within which the implantable substancedelivery device 12I and elongate delivery member or pusher 134 arepositioned. The substance delivery device 12I and elongate deliverymember or pusher 134 have lumens 132 and 136 extending longitudinallytherethrough. Thus, a guidewire GW may pass through the lumens 132 and136, thereby allowing the system to be advanced over a previouslyinserted guidewire. Thus, it is to be understood that, whereverfeasible, the substance delivery devices 12 of the present invention mayhave guidewire lumens or passageways extending therethrough.

FIGS. 12A-12E show one of many possible examples of procedures that maybe performed using the implantable substance delivery devices 12 of thepresent invention. This particular example shows a method for treatingsinusitis in a human or animal subject. In this subject, the sinusitisis due at least in part to impaired drainage from the sinus as a resultof an occlusion of the ostium OS that leads into the paranasal sinus.The ostium OS consists of thin bone B covered by mucosal tissue. Asshown in FIG. 12A, a guidewire such as a Guidant Hi-Torque Supracore 35Guide Wire is advanced through the ostium OS and into the paranasalsinus. As shown in FIG. 12B, a balloon catheter 200 such as the GuidantAgiltrac 0.035 Peripheral Dilatation Catheter having a balloon 202formed of relatively strong material such as polyethylene teraphthalateis then advanced over the guidewire GW to a position where the balloon202 is positioned within the ostium OS. Thereafter, as shown in FIG.12B, the balloon 202 is inflated so as to dilate the ostium OS possiblybreaking bone B that surrounds the ostium OS and creating an enlargedostium EOS. Thereafter, as shown in FIG. 12C, the balloon 202 isdeflated and the balloon catheter 200 is withdrawn and removed, leavingthe guidewire GW in place. Thereafter, a delivery catheter of any of thetype described herein is advanced over the guidewire GW and to deliveran empty implantable substance delivery device 12 i of the presentinvention within the enlarged ostium EOS such that a portion of thedevice 12 i extends into the sinus, as shown in FIG. 12D. In thisexample, the implantable substance delivery device 12 i is an over thewire type device 12 i having a fill tube 204, an intraostial portion 206which includes a self-expanding frame 208 and intrasinus portion 210. Asshown in FIG. 12E, after the implantable substance delivery device 12 ihas been positioned such that its intraostial portion is within theenlarged ostium EOS and its intrasinus portion is within the paranasalsinus, the delivery catheter and guidewire GW are removed and a quantityof the desired diagnostic or therapeutic substance (e, g, acorticosteroid, anti-inflammatory, antimicrobial, mucous modifying ormucolytic agent, or other agent or substance effective to treatsinusitis) is infused through the fill tube 204 into the device 12 i. Asshown in FIG. 12E, this causes the intrasinus portion 210 of the device12 i to swell or expand to an enlarged configuration that will not passout of the enlarged ostium EOS. Also, the intraostial portion 206 andframe 208 will enlarge to an expanded configuration that exerts outwardradial pressure against the enlarged ostium EOS for a period of timesufficient to allow the enlarged ostium OS and any broken bone BBtherein to heal and remodel to the enlarged diameter. Also, thesubstance(s) that was/were introduced into the device 12 i will diffuseout of the device 12 into the sinus at a desired rate, thereby providingpharmacological treatment for the infection, inflammation and/or otheraspects of the sinusitis. Thereafter the device 12 i may biodegradeand/or may be removed and the enlarged ostium will remain facilitatingnormal drainage from the sinus thereafter.

Another embodiment of the substance delivery device incorporates theaddition of a micropump to one or all of the drug containing chambers.The micropump would assist in active transport of the drug across themembrane. The delivery rate of this pump could be programmed ahead oftime or via remote electronics. Other methods of incorporatingmicromachinery or nanotechnology to enable pressure assisted transportcould be added to the substance delivery device. Another example wouldinclude a semi-permeable membrane where the reservoir volumecontinuously shrinks as drug is eluted to maintain a certain drivingpressure in the reservoir. This shrinkage could be due to elasticproperties of the membrane or due to mechanically limiting and changingthe space in the reservoir. These devices could be refillable.

The abovementioned embodiments may be used as spacing devices after aopen surgical, laparoscopic surgical or an interventional procedure.Further, these devices may be further coated with an anti-infectiveagent or may be constructed of a substance which is naturallybacteriostatic to reduce the likelihood of toxic-shock syndrome or otherdevice related infections. Such a naturally bacteriostatic materialwould be a biodegradable substance which, through the process ofbiodegradation, undergoes hydrolysis, releasing bacteriostaticsubstances such as hydrogen peroxide.

It is to be appreciated that the invention has been described hereabovewith reference to certain examples or embodiments of the invention butthat various additions, deletions, alterations and modifications may bemade to those examples and embodiments without departing from theintended spirit and scope of the invention. For example, any element orattribute of one embodiment or example may be incorporated into or usedwith another embodiment or example, unless to do so would render theembodiment or example unsuitable for its intended use. All reasonableadditions, deletions, modifications and alterations are to be consideredequivalents of the described examples and embodiments and are to beincluded within the scope of the following claims.

1. A method for using a transnasally insertable implantable substancedelivery device for delivering a diagnostic or therapeutic substance toa location within a paranasal sinus or paranasal sinus ostium of a humanor animal subject, said method comprising the steps of: A) providing adevice that comprises i) an expandable reservoir that is initiallysubstantially in a collapsed configuration, said collapsed configurationbeing sufficiently small to allow the reservoir, while in said collapsedconfiguration, to be inserted through a nostril of the subject andadvanced to said location within a paranasal sinus or paranasal sinusostium, said reservoir being thereafter expandable to an expandedconfiguration; ii) a tube extending from said reservoir, said tubehaving a lumen through which a quantity of the substance may beintroduced into the reservoir; iii) a barrier through which thesubstance will elute from the reservoir, thereby causing the substanceto be delivered to said location within the paranasal sinus or paranasalsinus ostiun; and iv) a closure apparatus for preventing the substancefrom backflowing out of the tube after the substance has been introducedinto the reservoir; B) inserting the device, with the reservoir in thecollapsed configuration, through a nostril of the subject andpositioning the reservoir within a paranasal sinus or paranasal sinusostim; C) introducing a quantity of the substance through the tube andinto the reservoir, thereby causing the reservoir to assume the expandedconfiguration; and D) delivering at least some of the substance out ofthe reservoir to said location within the paranasal sinus or paranasalsinus ostium by leaving the device implanted within the paranasal sinusor paranasal sinus ostium for a period of time such that the substancewill elute through the barrier.
 2. A method according to claim 1 whereinthe reservoir comprises a hollow cavity into which the substance isintroduced.
 3. A method according to claim 2 wherein at least a portionof said reservoir comprises a porous material that becomes laden withthe substance.
 4. A method according to claim 3 wherein the porousmaterial is selected from the group consisting of: a sponge flexiblepolymer foams; biodegradable polymer foams; non-biodegradable polymerfoams; porous PLLA; porous PLGA; porous hydrogel; polyvinyl alcohols;silicone foams; polytetrafluoroethylene; expandedpolytetraflurorethylene; latex; and nylon.
 5. A method according toclaim 2 wherein, in addition to said hollow cavity, the reservoirfurther comprises a porous material which will hold a quantity of thesubstance.
 6. A method according to claim 5 wherein the porous materialis located adjacent to the hollow cavity such that the substance may beinitially introduced into the hollow cavity and thereafter absorbed ortransported into the porous material.
 7. A method according to claim 1wherein the closure apparatus comprises apparatus for clamping,clipping, ligating, tying or compressing the tube after the substancehas been introduced into the reservoir.
 8. A method according to claim 1further comprising the step of: E) cutting away a portion of the tube sothat the tube does not protrude outside of the subject's nose.
 9. Amethod according to claim 1 further comprising the step of: E) removingthe substance delivery device.
 10. A method according to claim 9 whereinthe substance delivery device further comprises a graspable member andwherein the method further comprises the step of grasping and pullingthe graspable member to facilitate removal of the device.
 11. A methodaccording to claim 1 wherein the device is configured such that, when inthe expanded configuration, the device includes at least one flowchannel through which mucous or other biological fluid may drain andwherein the device is positioned such that mucous or other biologicalfluid drains through said at least one flow channel while the device isimplanted.
 12. A method according to claim 1 wherein the device has anintraostial portion that is positioned within a paranasal sinus ostiumand an intrasinus portion that is positioned within a paranasal sinus,there being at least one indentation in the intraostial portion of thedevice and wherein the device is positioned such that at least a portionof the ostium is received within said at least one indentation when thereservoir is in its expanded configuration.
 13. A method according toclaim 1 wherein a delivery catheter system is used to deliver thesubstance delivery device, the delivery catheter system comprising: acatheter that has a lumen and a distal opening, said transnasallyinsertable device being positioned within the lumen of the catheter; anda member positioned within the lumen of the catheter proximal to thetransnasally insertable device; and wherein the method further comprisesthe step of: moving at least one of said catheter and said memberrelative to the other so as to expel the substance delivery device outof the distal opening of the catheter.